Idiopathic nephrotic syndrome (NS) is the most common glomerular disease in children. The two most common histopathological findings on invasive biopsy are minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS). The prognosis of children with NS depends on the underlying histopathology and can be predicted by response to steroid treatment.
Steroid resistant nephrotic syndrome (SRNS) and biopsy-proven focal segmental glomerulosclerosis (FSGS) are significantly associated with poor outcome. FSGS is a pathologic diagnosis that is steroid resistant (SRNS) in approximately 70% of cases. While total numbers of patients diagnosed with NS have remained steady, SRNS is on the rise, as marked by the increase in incidence of FSGS in children. FSGS is the most common primary glomerular disease leading to end-stage renal disease (ESRD) in children. An additional complication in patients with FSGS leading to ESRD is the high rate of recurrence (30-40%) following transplant.
An invasive renal biopsy remains the standard of diagnosis in adults. Children, however are not typically biopsied at presentation, unless they have atypical features, because response to steroids is a better predictor than histology of long term prognosis. Single renal biopsies in children tend to under diagnose FSGS, because of the focal nature of the disease, and their effectiveness in influencing outcome remains under debate.
Of the patients diagnosed with idiopathic nephrotic syndrome, over 90% of children with minimal change disease will respond to steroids and 10% will be steroid resistant. The common treatment modality for idiopathic nephrotic syndrome consists of steroids which have proved to be an adequate therapy for idiopathic nephrotic syndrome, although have remained futile in the treatment of the most common resistant forms, FSGS. Steroid responsiveness has remained the prognostic modality for the identification of FSGS in spite of invasive renal biopsies being the gold standard after failed responsive to corticosteroids [1]. Prior to the diagnosis of FSGS, all patients who present with nephrotic syndrome are presumed to have steroid-sensitive nephrotic syndrome, MCNS. Typical steroid therapy includes 2 mg/kg/day for 6-8 weeks followed by steroid taper over the course of several weeks to months and eventual discontinuation of steroids per the Ponticelli protocol[2]. This alone allows the patient to suffer possible consequences of steroid toxicity. Osteoporosis, adrenal suppression, hyperglycemia, dyslipidemia, cardiovascular disease, Cushing's syndrome, psychiatric disturbances and immunosuppression are among the more serious side effects noted with systemic corticosteroid therapy, particularly when used at high doses for prolonged periods [3]. In addition to the direct toxic side effects of steroids, patients are at risk to progressive renal injury that is only delayed by the unnecessary exposure to steroids. It has been demonstrated that if a patient has not responded to steroids by 6 months, treatment beyond this duration was not beneficial. On the other hand, management of patients with FSGS poses a therapeutic challenge, justifying the need for a more beneficial therapeutic alternative.
There are currently no diagnostic tests that accurately predict steroid responsiveness in pediatric NS or distinguish SRNS from SSNS. As such, the initial prolonged daily course of high dose corticosteroids serves both a therapeutic and diagnostic purpose. Therefore, identification of urinary biomarkers that predict steroid responsiveness or differentiate SR/FSGS from SS/MCD would benefit patients with SRNS by potentially avoiding exposure to high-dose corticosteroids.
The instant disclosure seeks to address one or more of these needs in the art.